Acatinib brings hope to patients with ibrutinib intolerance to R/R CLL

Inhibitors targeting Bruton's tyrosine kinase (BTK) can inhibit B cell receptor (BCR) signaling, which can effectively treat patients with chronic lymphocytic leukemia (CLL)
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The application of BTK inhibitors represented by Ibrutinib has significantly improved the effective rate of CLL patients and improved long-term survival
.

Acalabrutinib is a selective oral BTK inhibitor with fewer off-target effects and may improve safety characteristics.
It has been approved for the treatment of CLL patients
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Based on this, some researchers have explored the efficacy and safety of acatinib in patients with R/R CLL who are intolerant to the treatment of ibrutinib and whose disease continues to be active
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Research method This multi-center, single-agent, phase II clinical study enrolled adult patients with CLL who were intolerant to ibrutinib and could not choose purine analog based therapy
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Ibrutinib intolerance is defined as A) discontinuation of ibrutinib treatment due to a grade 3 or 4 adverse event (AE), or B) occurrence of a grade 2 AE related to ibrutinib treatment, lasting for at least 2 weeks or There were at least 2 recurrences.
Although the best supportive treatment was taken, whether the dose of Ibrutinib should be reduced or interrupted
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After discontinuing ibrutinib, patients must meet the CLL International Symposium (iwCLL) 2008 disease progression (PD) criteria as a marker of continued disease activity and have not received other CLL treatments
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The primary end point is the overall patient response rate (ORR) assessed by the investigator according to the iwCLL 2008 standard
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Research results 1.
Baseline situation of patients The study was conducted from March 23, 2016 to August 2, 2017, and a total of 60 patients were enrolled
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The median age is 69.
5 years (range: 43-88 years), and the median time from diagnosis to the first administration of the study drug is 103.
2 months (range: 10.
3-307.
9 months)
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The patients with del(17p) accounted for 28%, and the patients with Rai stage III or IV accounted for 52%
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The patient's baseline and disease characteristics are shown in Table 1
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The median of previous treatments was 2 (range: 1-10)
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All patients had previously received ibrutinib treatment, 50 cases (83%) received ibrutinib monotherapy, 10 cases (17%) received ibrutinib combined with another drug, 43 cases (72 %) Patients were exposed to anti-CD20 monoclonal antibodies, 36 patients (60%) had previously received systemic chemotherapy
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Table 1: Baseline characteristics of patients 2.
Efficacy The ORR of patients after acatinib treatment was 73% (95% CI: 60%-84%)
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The subgroup of patients with del(17p) also had a similar ORR of 71% (95% CI: 44%-90%)
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Overall, the ORR of all patients, including those with PR with lymphocytosis (PRL), was 78% (95% CI: 66%-88%), including 3 (5%) patients with complete remission (CR), 2 There were 3 (3%) CR (CRi) patients with incomplete blood cell recovery, 39 (65%) PR patients, and 3 (5%) PRL patients
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Of the 13 patients who did not achieve remission, 4 (7%) had stable disease (SD), 1 (2%) had disease progression (PD); 6 (10%) patients had first remission within 3 months The treatment was discontinued before the evaluation and the evaluation could not be performed, and 2 cases (3%) could not be evaluated for the efficacy
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For the 6 unevaluable patients, 3 were discontinued due to AE, and 3 were discontinued due to the patient or doctor's decision (1 and 2 patients, respectively)
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The median duration of response (DOR) for the overall patient was not reached, and the estimated 24-month DOR rate was 81% (95% CI: 66%-90%) and 78% (95% CI: when PRL patients were included) 63-88%); the estimated 36-month DOR rate was 65% (95% CI: 46-79%) and 64% (95% CI: 45-77%) when PRL patients were included (Figure 1)
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Figure 1: The patient’s DOR status.
The median progression-free survival (PFS) has not been reached; the estimated 24-month and 36-month PFS rates are 72% (95% CI: 58%-82%) and 58% ( 95% CI: 42%-71%) (Figure 2A)
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The patient’s median overall survival (OS) was not reached; the estimated 24-month and 36-month OS rates were 81% (95% CI: 68%-89%) and 78% (95% CI: 65%), respectively -87%) (Figure 2B)
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Sixteen patients (27%) started CLL follow-up treatment, and the median time to next treatment (TTNT) was 44 months (95% CI: 27-unestimable)
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Figure 2: Patients' PFS and OS status 3.
Safety The most common AEs of any grade in the treatment of acatinib were diarrhea (53%), headache (42%), contusion (40%), dizziness (33%), upper Respiratory tract infection (33%) and cough (30%) (Table 2)
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Ten patients (16.
7%) had AEs that led to the discontinuation of Akatinib, including infectious pneumonia, diarrhea, headache, endometrial cancer, stomatitis, subdural hematoma, cerebrovascular accident, elevated transaminases, and lung scales Shape cell carcinoma
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Only one patient discontinued acatinib due to the same AE (diarrhea) that caused the previous discontinuation of ibrutinib
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Table 2: Conclusion of the study on the occurrence of AEs in patients The results of this study indicate that acatinib is a safe and effective option for R/R CLL patients who cannot tolerate ibrutinib
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Acatinib is an important treatment option for this population, and more CLL patients will benefit from BTK inhibitor treatment
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References: Kerry A Rogers, Philip A Thompson, John N Allan, et al.
Phase II study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia.
Haematologica.
2021 Sep 1;106(9):2364-2373 .
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